Functional Roles of Neuroimmune Factors in Mediating Behavior. Ethanol abuse at all life-stages can result in significant disability, and alcoholism has tremendous personal and societal consequences. Ethanol abuse at each of these life-stages is associated with inflammation in the central nervous system (CNS). This may contribute to neurodegeneration and impaired neurological function associated with excessive alcohol consumption. In addition, intriguing recent studies demonstrate that pro- inflammatory molecules including cytokines and chemokines modulate addiction to alcohol, which has resulted in a paradigm shift linking immune response to addictive behavior. The proposed studies will address a critical gap in our knowledge concerning the role of neuroinflammation in mediating ethanol-induced neurodegeneration throughout life. The general hypothesis of the proposed studies is that toll-like receptors (TLRs) expressed by resident CNS microglia respond to "danger signals" produced following ethanol exposure in the CNS resulting in the production of pro-inflammatory cytokines and chemokines that both modulate neurodegeneration as well as alcohol addiction. This will be tested in parallel in mice in vivo and in vitro in primary cultures, utilizing animals with targeted deletion of key TLR signaling molecules. f Specific Aim 1: Determine the mechanisms by which microglial TLRs modulate response to ethanol and neurodegeneration. f Specific Aim 2: Determine the effects of TLRs in modulating ethanol-induced neurodegeneration in vivo at different life-stages. f Specific Aim 3: Determine the effects of TLRs in modulating ethanol-induced neuroinflammation in vivo at different life-stages. PUBLIC HEALTH RELEVANCE: The proposed studies will determine the mechanisms by which TLRs expressed by microglia modulate ethanol induced neurodegeneration in the nervous system at different life-stages. These studies may have important implications concerning treatments designed to protect the brain from toxic effects of ethanol as well as